November 30, 2013
Protein Analysis Could Lead To Hepatitis C Vaccine
redOrbit Staff & Wire Reports - Your Universe Online
A hepatitis C vaccine is one step closer thanks to the efforts of scientists at The Scripps Research Institute (TSRI), who have managed to discover unexpected structural features of a protein used by the virus to infect liver cells.
The study authors, whose work appears in Friday’s edition of the journal Science, state any successful hepatitis C vaccine would most likely target this protein, which is known as E2 envelope glycoprotein. Rare antibodies capable of binding E2 in ways that can neutralize a vast array of different viral strains have already been isolated in patients by scientists, they added.
“We're excited by this development,” senior author Dr. Ian A. Wilson, the Hansen Professor of Structural Biology at TSRI, said in a statement. He added that it took him and his TSRI colleagues Dr. Mansun Law and Dr. Andrew B. Ward six years of “painstaking work” to complete a high resolution structure of the protein. They now intend to create vaccines that can mimic the structural details of those binding sites.
According to the Institute, the global spread of hepatitis C has resulted in a desperate need for an effective vaccine against the virus. The pathogen, which was once geographically isolated, has found its way throughout the world, primarily due to blood transfusions, the use of unsterilized medical equipment and the re-use of hypodermic needles. While hospitals have screened for the virus for approximately two decades, there are believed to be up to 200 million people worldwide infected with hepatitis C, including over three million in the US alone.
“HCV was able to spread so widely because it typically causes few or no symptoms when it infects someone. In many cases it establishes a long-term infection of the liver, damaging it slowly for decades – until liver cirrhosis and/or cancer develop,” TSRI explained. The research was funded in part by the National Institutes of Health and the Skaggs Institute of Chemical Biology.
The disease, which according to Law is a “silent killer,” is typically fatal unless a patient undergoes a costly and high-risk liver transplantation procedure. Some antiviral medications can treat and even cure chronic hepatitis C infection, but the most effective ones are extremely expensive, and often those who are infected do not realize they have the virus and require medical attention. A vaccine could prevent new infections, ending the pandemic.
“It could be given to people when they're young and healthy, and they'd never have to worry about developing HCV-related liver diseases,” Ward said. However, unlike HIV and other viruses, hepatitis C utilizes several different effective countermeasures to evade an immune system, including rapidly-mutating regions on the E2 protein that makes sure antibodies that are effective against one strain are not ineffective against others.
The TSRI researchers set out to analyze the high-resolution atomic structure of the virus in order to help overcome these countermeasures. However, according to the study authors, that has been a difficult task to attempt, let alone complete. It took dozens of experiments to find the right way to modify E2, making it so the protein aggregates less readily while making sure that its antibody-binding sites are maintained. Ward called it “a Herculean effort” because hepatitis C is “one of the most difficult and unstable viral envelope proteins around.”
“In the end, the team succeeded, using a slightly altered version of E2 – the E2 core – with some of its glycans (sugar molecules) and outer variable and stalk segments removed,” the Institute said. “The scientists were then able to obtain the high-resolution structure of the protein while it was bound to a known broadly neutralizing antibody developed at TSRI. The scientists then followed up by imaging a more complete version of E2 using electron microscopy to extend the structural model.”
Image 2 (below): This is the new picture of hepatitis C's E2 protein, which the virus uses to infect liver cells, will aid in the design of a vaccine against the disease. Credit: The Scripps Research Institute